Age at diabetes diagnosis, genetic susceptibility and dementia risk: a prospective study of 13,126 participants from the UK Biobank

(1) To investigate the association between age at diabetes diagnosis and the incidence of all-cause dementia (ACD), Alzheimer’s disease (AD), and vascular dementia (VD) in individuals with diabetes. (2) To assess the relationship among age at diabetes diagnosis, dementia polygenic risk score (PRS), APOE ε4 carrier status, and risk of ACD. In a large, population-based cohort with a median follow-up of 13.4 years, participants were stratified by age at diabetes diagnosis (< 50, 50–60, and > 60 years). Cox proportional hazards models were used, adjusted for multiple covariates. Genetic risk was assessed using dementia PRS, and APOE ε4 carrier status was considered in the analysis. (1) Individuals diagnosed at ages 50–60 (hazard ratio (HR) = 0.71, 95% CI: 0.55–0.93, P = 0.0117) and > 60 years (HR = 0.59, 95% CI: 0.44–0.79, P < 0.001) had significantly lower ACD risk compared to those diagnosed at age < 50 years. (2) Genetic risk stratification: among participants with intermediate and high dementia PRS, diabetes diagnosis at age > 60 years was associated with reduced ACD risk (intermediate PRS: HR = 0.66, 95% CI: 0.44–0.97, P = 0.0035; high PRS: HR = 0.46, 95% CI: 0.26–0.83, P = 0.009). (3) APOE ε4 carrier analysis: in APOE ε4 carriers, diagnosis of diabetes at > 60 years (HR = 0.43, 95% CI: 0.29–0.64, P < 0.001) and at 50–60 years (HR = 0.69, 95% CI: 0.40–0.85, P = 0.005) was associated with a significantly reduced risk of ACD compared to diagnosis at age < 50 years. Later onset of diabetes (age ≥ 50) is associated with a lower risk of ACD, particularly among individuals with higher genetic susceptibility to dementia, including APOE ε4 carriers. These findings highlight the importance of early diabetes management and targeted lifestyle interventions in high-risk populations to potentially reduce dementia risk.